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Human Molecular Genetics Advance Access published online on March 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm045
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PGC-1{alpha}/ß Upregulation is Associated with Improved Oxidative Phosphorylation in Cells Harboring Nonsense MtDNA Mutations

Sarika Srivastava1, John N. Barrett2 and Carlos T. Moraes1,3,*

1 Department of Neurology, University of Miami, Miller School of Medicine 2 Department of Physiology & Biophysics, University of Miami, Miller School of Medicine 3 Department of Cell Biology & Anatomy, University of Miami, Miller School of Medicine

* Correspondence should be addressed to: Carlos T. Moraes, Ph.D. University of Miami School of Medicine, 1095 NW 14th Terrace. Miami, FL 33136, (305)243-5858 FAX: (305)243-3914, cmoraes{at}med.miami.edu

Received November 29, 2006; Revised February 20, 2007; Accepted February 26, 2007

We have studied the functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. Surprisingly, these cells had an efficient oxidative phosphorylation (OXPHOS), however, when mitochondria from these cells were transferred to an osteosarcoma nuclear background (osteosarcoma cybrids), the rate of respiration markedly declined suggesting that the phenotypic expression of the mtDNA mutations were prevented by the colorectal tumor nuclear background. We found that there was a significant increase in the steady-state levels of PGC-1{alpha} and PGC-1ß transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviral mediated overexpression of PGC-1{alpha} and PGC-1ß in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1{alpha}/ ß coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1{alpha} and PGC-1ß in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.


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